Binder Natalie K, de Alwis Natasha, Fato Bianca R, Beard Sally, Mangwiro Yeukai T M, Kadife Elif, Brownfoot Fiona, Hannan Natalie J
Therapeutics Discovery & Vascular Function in Pregnancy Group, University of Melbourne, Mercy Hospital for Women, Heidelberg 3084, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Australia.
Nutrients. 2025 May 5;17(9):1586. doi: 10.3390/nu17091586.
Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, with obesity recognised as a significant risk factor. However, the direct contribution of obesity to the pathophysiology underpinning preeclampsia remains unclear.
This study aimed to develop and characterise a diet-induced obese mouse model with superimposed preeclampsia to better understand the impact of obesity on disease pathogenesis.
Female mice were fed either standard rodent chow or a high-fat diet from weaning. At 8 weeks of age, mice were mated. Pregnant mice were treated with L-N-Nitro arginine methyl ester (L-NAME; to block nitric oxide production) from gestational day (D)7.5 to D17.5 to induce a preeclampsia-like phenotype. Blood pressure was measured on D14.5 and D17.5, followed by the collection of maternal and fetal tissues for histological, biochemical, and molecular analyses.
Obese dams exhibited significantly increased body, fat pad, and liver weights compared to lean controls. While L-NAME induced hypertension in the control mice, contrary to expectations, the L-NAME-induced hypertension was partially attenuated in obese dams, with significantly lower systolic and diastolic blood pressures at D14.5 and reduced systolic pressure at D17.5. Fetal weights were comparable between groups, however, placentas were significantly heavier with obesity. Endothelial function, inflammatory markers, and renal gene expression patterns suggested distinct physiological adaptations in obese preeclamptic-like mice.
These findings challenge the prevailing assumption that obesity drives hypertension, endothelial dysfunction, and inflammatory markers. The differential vascular and physiological responses observed in the obese dams highlight the complexity of obesity-preeclampsia interactions and underscore the need for refined preclinical models to disentangle mechanistic contributions. This work has implications for personalised management strategies and targeted therapeutic interventions in obese pregnancies at risk of preeclampsia.
子痫前期是孕产妇和胎儿发病及死亡的主要原因，肥胖被认为是一个重要的危险因素。然而，肥胖对子痫前期病理生理的直接影响仍不清楚。
本研究旨在建立并表征一种叠加子痫前期的饮食诱导肥胖小鼠模型，以更好地了解肥胖对疾病发病机制的影响。
雌性小鼠从断奶开始分别喂食标准啮齿动物饲料或高脂饮食。8周龄时，小鼠进行交配。怀孕小鼠从妊娠第（D）7.5天至D17.5天用L-N-硝基精氨酸甲酯（L-NAME；以阻断一氧化氮生成）处理，以诱导子痫前期样表型。在D14.5和D17.5测量血压，随后收集母体和胎儿组织进行组织学、生化和分子分析。
与瘦对照组相比，肥胖母鼠的体重、脂肪垫重量和肝脏重量显著增加。虽然L-NAME在对照小鼠中诱导了高血压，但与预期相反，L-NAME诱导的高血压在肥胖母鼠中部分减轻，在D14.5时收缩压和舒张压显著降低，在D17.5时收缩压降低。各组间胎儿体重相当，然而，肥胖时胎盘明显更重。内皮功能、炎症标志物和肾脏基因表达模式表明肥胖子痫前期样小鼠存在不同的生理适应性。
这些发现挑战了肥胖导致高血压、内皮功能障碍和炎症标志物的普遍假设。在肥胖母鼠中观察到的不同血管和生理反应突出了肥胖与子痫前期相互作用的复杂性，并强调需要完善的临床前模型来阐明机制作用。这项工作对有子痫前期风险的肥胖妊娠的个性化管理策略和靶向治疗干预具有启示意义。
